scholarly journals Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer

2018 ◽  
Vol 25 (9) ◽  
pp. 807-819 ◽  
Author(s):  
Matias Knuuttila ◽  
Arfa Mehmood ◽  
Jenni Mäki-Jouppila ◽  
Henrik Ryberg ◽  
Pekka Taimen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Alternative Pathway ◽  
Prostate Tissue ◽  
Cancer Therapies ◽  
Serum Samples ◽  
Androgen Metabolism ◽  
Tissue Specimens ◽  
Regulated Gene Expression ◽  
Benign Prostate

Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (P < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG-negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and -negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.

scholarly journals Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Renato Polimanti ◽  
Talisa K Silzer ◽  
Frank R Wendt ◽  
Ranajit Chakraborty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Repair ◽  
Copy Number Variation ◽  
Whole Blood ◽  
Genetic Variants ◽  
Copy Number ◽  
Prostate Tissue ◽  
Number Variation ◽  
Regulated Gene Expression

Abstract BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

scholarly journals Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Gita A. Pathak ◽  
Renato Polimanti ◽  
Talisa K. Silzer ◽  
Frank R. Wendt ◽  
Ranajit Chakraborty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Repair ◽  
Copy Number Variation ◽  
Whole Blood ◽  
Genetic Variants ◽  
Copy Number ◽  
Prostate Tissue ◽  
Number Variation ◽  
Regulated Gene Expression

Abstract Background Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. Methods We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). Results In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. Conclusions We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

scholarly journals Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Renato Polimanti ◽  
Talisa K Silzer ◽  
Frank R Wendt ◽  
Ranajit Chakraborty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Repair ◽  
Copy Number Variation ◽  
Whole Blood ◽  
Genetic Variants ◽  
Copy Number ◽  
Prostate Tissue ◽  
Number Variation ◽  
Regulated Gene Expression

Abstract BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

scholarly journals Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 537 ◽  
Author(s):  
Renuka Sriram ◽  
Mark Van Criekinge ◽  
Justin DeLos Santos ◽  
Fayyaz Ahamed ◽  
Hecong Qin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Magnetic Resonance ◽  
Gleason Score ◽  
Prostate Tissue ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
High Grade ◽  
Metabolic Alterations ◽  
Ldh Activity ◽  
Benign Prostate

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR.

Proteomics analysis of malignant and benign prostate tissue by 2D DIGE/MS reveals new insights into proteins involved in prostate cancer

The Prostate ◽  
2015 ◽  
Vol 75 (14) ◽  
pp. 1586-1600 ◽  
Author(s):  
Katarina Davalieva ◽  
Ivana Maleva Kostovska ◽  
Sanja Kiprijanovska ◽  
Katerina Markoska ◽  
Katerina Kubelka-Sabit ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Tissue ◽  
Proteomics Analysis ◽  
2D Dige ◽  
Benign Prostate

Differential gene expression in prostate tissue according to vasectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 298-298
Author(s):  
Kathryn M Wilson ◽  
Travis Gerke ◽  
Ericka Ebot ◽  
Jennifer A Sinnott ◽  
Jennifer R. Rider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Diagnosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Prostate Tissue ◽  
Gene Set Enrichment ◽  
Normal Prostate ◽  
Gene Sets ◽  
Normal Prostate Tissue

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.

High Selenium Reduces NF-κB-Regulated Gene Expression in Uninduced Human Prostate Cancer Cells

2007 ◽  
Vol 58 (2) ◽  
pp. 197-204 ◽  
Author(s):  
Merrill J. Christensen ◽  
Edward T. Nartey ◽  
Aimee L. Hada ◽  
Russell L. Legg ◽  
Brett R. Barzee
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
High Selenium ◽  
Regulated Gene Expression
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